Studies conservatively estimate that between 10 and 20% of military service members deployed to combat in Iraq (Operation Iraqi Freedom;OIF)) and Afghanistan (Operation Enduring Freedom;OEF) develop significant symptoms of Posttraumatic Stress Disorder (PTSD) post deployment. Combat veterans who develop PTSD are at increased risk for a number of additional health and mental health problems, and are increasingly presenting to the Veteran's Health Administration (VHA) for care. However, not all veterans exposed to combat are equally likely to develop PTSD. A number of factors, including environmental and genetic factors and their interaction, are associated with risk/resilience to PTSD. Environmental risk factors for PTSD can be categorized as: pre-trauma, trauma-related characteristics and post-trauma factors. Within these categories, three well studied risk factors are: 1) level of pre-trauma exposure to adverse/traumatic events, including childhood abuse 2) severity/perception of life threat of the trauma and 3) post trauma social support. Although we know that PTSD has a significant heritable component, research on the specific genetic variations conferring risk/resilience for PTSD is limited. There is even less available data on the potential interaction of environmental variables with genetic factors in the prediction of PTSD. However, several recent papers, including work from our groups, have identified gene by environment interactions predicting risk/resilience to PTSD for both the Serotonin Transporter Linked Polymorphism Region (5-HTTLPR) and the FKBP5 genes when in combination with environmental factors, including childhood abuse, traumatic exposure, and social support. These genes are excellent candidates for understanding risk for PTSD, both because of their involvement in the stress response, as well as their association, in prior research, with symptoms and biomarkers of mood and other anxiety disorders. The majority of the studies inclusive of environmental, genetic or gene x environment risk factors for PTSD focus on non-combat related trauma exposure, with even fewer focusing on recently returned combat veterans. The goal of the proposed study is to extend the above research findings on environmental, genetic and gene x environment predictors of PTSD to a population of N=800 combat exposed OEF/OIF veterans (400 meeting PTSD diagnosis or with significant symptoms of PTSD and 400 not meeting PTSD diagnosis) seeking VHA care. In addition, we have included a secondary aim focused on evaluating the above environmental, genetic, and gene x environment variables in predicting PTSD-related biomarkers in a combat-related psychosocial stress task and during a fear conditioning paradigm. Our long-term goal is to combine an understanding of the environmental and genetic determinants of risk/resilience to PTSD to develop strategies towards mitigating risk factors and promoting resilience to traumatic stressors, particularly in high-risk populations such as combat veterans. PUBLIC HEALTH RELEVANCE: Between 10 - 20% of military service members deployed to combat in Iraq (Operation Iraqi Freedom;OIF)) and Afghanistan (Operation Enduring Freedom;OEF) develop significant symptoms of Posttraumatic Stress Disorder (PTSD). These veterans are increasingly presenting to the Veteran's Health Administration (VHA) for health care, including PTSD treatment. Veterans who develop PTSD are at increased risk for a number of additional physical and mental health problems, including an increased risk for suicide. However, not all veterans exposed to combat are equally likely to develop PTSD. This proposal seeks to examine the genetic and environmental determinants of risk and resilience to PTSD in OEF/OIF combat veterans. It is anticipated that these findings may be helpful towards mitigating risk factors and promoting resilience to traumatic stressors.